BR112016008378B1 - Compostos de quinolina seletivamente substituídos ou sal dos mesmos, e composição farmacêutica contendo os ditos compostos - Google Patents
Compostos de quinolina seletivamente substituídos ou sal dos mesmos, e composição farmacêutica contendo os ditos compostos Download PDFInfo
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- BR112016008378B1 BR112016008378B1 BR112016008378-4A BR112016008378A BR112016008378B1 BR 112016008378 B1 BR112016008378 B1 BR 112016008378B1 BR 112016008378 A BR112016008378 A BR 112016008378A BR 112016008378 B1 BR112016008378 B1 BR 112016008378B1
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- BR
- Brazil
- Prior art keywords
- methylpiperidin
- cyanoquinolin
- amino
- mmol
- methyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 title claims description 111
- 150000003839 salts Chemical class 0.000 title claims description 47
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims description 75
- -1 dioxidothiopyranyl Chemical group 0.000 claims description 72
- 206010025135 lupus erythematosus Diseases 0.000 claims description 38
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 18
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 102000045715 human TLR7 Human genes 0.000 claims description 14
- 230000004913 activation Effects 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 230000001419 dependent effect Effects 0.000 claims description 9
- 102000003945 NF-kappa B Human genes 0.000 claims description 6
- 108010057466 NF-kappa B Proteins 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 5
- 239000012091 fetal bovine serum Substances 0.000 claims description 5
- MPGCORKREKQAST-WCQYABFASA-N 5-[(3r,5s)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carbonitrile Chemical compound C1[C@@H](C)C[C@@H](N)CN1C1=CC=C(C#N)C2=NC=CC=C12 MPGCORKREKQAST-WCQYABFASA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000004020 luminiscence type Methods 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 206010063663 Neuropsychiatric lupus Diseases 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000007747 plating Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims 3
- LOWLIXJVOKQXRP-VPWXQRGCSA-N (2S)-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methyl-2-(methylamino)butanamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1C[C@@H](C[C@@H](C1)C)NC([C@H](C(C)C)NC)=O LOWLIXJVOKQXRP-VPWXQRGCSA-N 0.000 claims 2
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- GBSNGTLITPOAQM-DKZVUGQWSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)C1=CC=CC=C1 GBSNGTLITPOAQM-DKZVUGQWSA-N 0.000 claims 1
- SBQCLFUIJZXTLT-XTQGRXLLSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)C(F)(F)F SBQCLFUIJZXTLT-XTQGRXLLSA-N 0.000 claims 1
- MIYMFVVWFJYWDT-LESCRADOSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-ethylsulfanylpropanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CSCC MIYMFVVWFJYWDT-LESCRADOSA-N 0.000 claims 1
- KKKANZIUJZIJFN-JGGQBBKZSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-hydroxypropanamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CO KKKANZIUJZIJFN-JGGQBBKZSA-N 0.000 claims 1
- SXCUBAMGHCAYRX-UCNVEGJOSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-phenylpropanamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC1=CC=CC=C1 SXCUBAMGHCAYRX-UCNVEGJOSA-N 0.000 claims 1
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- HKBSADXDDOGWRG-KVSKMBFKSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-4-methylpentanamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC(C)C HKBSADXDDOGWRG-KVSKMBFKSA-N 0.000 claims 1
- KKQHXOGKPYDXJU-JGGQBBKZSA-N (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]butanediamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC(=O)N KKQHXOGKPYDXJU-JGGQBBKZSA-N 0.000 claims 1
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- IVTDUBWZVTXNBH-QTGUNEKASA-N (2R)-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(methylamino)-3-phenylpropanamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1C[C@@H](C[C@@H](C1)C)NC([C@@H](CC1=CC=CC=C1)NC)=O IVTDUBWZVTXNBH-QTGUNEKASA-N 0.000 claims 1
- GLHTYUAPUWZVHX-YXJHDRRASA-N (2R)-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]pyrrolidine-2-carboxamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC=12)N1C[C@@H](C[C@@H](C1)C)NC(=O)[C@@H]1NCCC1 GLHTYUAPUWZVHX-YXJHDRRASA-N 0.000 claims 1
- YPPRSVPYNOKVOW-FHKFTOANSA-N (2R,3S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-hydroxybutanamide Chemical compound N[C@@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)[C@H](C)O YPPRSVPYNOKVOW-FHKFTOANSA-N 0.000 claims 1
- AUHYXZSAEUYFAD-BJJXKVORSA-N (2S)-2-amino-N'-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]butanediamide Chemical compound N[C@@H](CC(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)C(=O)N AUHYXZSAEUYFAD-BJJXKVORSA-N 0.000 claims 1
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- CQZCCOHOBPOSTD-YYFZDKIDSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)C(C)(C)C CQZCCOHOBPOSTD-YYFZDKIDSA-N 0.000 claims 1
- UWWQBBSRPFDUGK-GMBSWORKSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-(1,3-thiazol-4-yl)propanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC=1N=CSC=1 UWWQBBSRPFDUGK-GMBSWORKSA-N 0.000 claims 1
- ZLRSIGBLBQPCOY-YJLNNSPDSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-(1H-imidazol-5-yl)propanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC1=CN=CN1 ZLRSIGBLBQPCOY-YJLNNSPDSA-N 0.000 claims 1
- JWJXHAJVGFRZAO-NBCNXNJRSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-(4-hydroxyphenyl)propanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC1=CC=C(C=C1)O JWJXHAJVGFRZAO-NBCNXNJRSA-N 0.000 claims 1
- NJWZTPBTBUXEBK-LXZKKBNFSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methoxypropanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)COC NJWZTPBTBUXEBK-LXZKKBNFSA-N 0.000 claims 1
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- BTGUTCQGVZGUTP-SCWSEQNSSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-pyridin-3-ylpropanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC=1C=NC=CC=1 BTGUTCQGVZGUTP-SCWSEQNSSA-N 0.000 claims 1
- YLJJBMAGZFQOSM-SCWSEQNSSA-N (2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]-3-pyridin-4-ylpropanamide Chemical compound N[C@H](C(=O)N[C@H]1CN(C[C@H](C1)C)C1=C2C=CC=NC2=C(C=C1)C#N)CC1=CC=NC=C1 YLJJBMAGZFQOSM-SCWSEQNSSA-N 0.000 claims 1
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- NJTBNHUTGHYSNP-DZGCQCFKSA-N 2-[[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-N-methylacetamide Chemical compound C(#N)C=1C=CC(=C2C=CC=NC12)N1C[C@@H](C[C@@H](C1)C)NCC(=O)NC NJTBNHUTGHYSNP-DZGCQCFKSA-N 0.000 claims 1
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Images
Classifications
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Plural Heterocyclic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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WO2013096194A1 (en) * | 2011-12-22 | 2013-06-27 | Merck Patent Gmbh | Novel heterocyclic carboxamides as modulators of kinase activity |
PL3057964T3 (pl) | 2013-10-14 | 2020-05-18 | Eisai R&D Management Co., Ltd. | Selektywnie podstawione związki chinolinowe |
MX363708B (es) | 2013-10-14 | 2019-03-29 | Eisai R&D Man Co Ltd | Compuestos de quinolina selectivamente sustituidos. |
EP3889146A1 (en) | 2015-12-17 | 2021-10-06 | Merck Patent GmbH | Polyheterocyclic tlr7/8 antagonists and their uses for treating immune disorders |
JP7125385B2 (ja) * | 2016-08-08 | 2022-08-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Tlr7/8アンタゴニストおよびそれらの使用 |
EP4059934A1 (en) | 2016-09-09 | 2022-09-21 | Novartis AG | Compounds and compositions as inhibitors of endosomal toll-like receptors |
CN110023495A (zh) | 2016-10-14 | 2019-07-16 | 精密生物科学公司 | 对乙肝病毒基因组中的识别序列特异性的工程化大范围核酸酶 |
CA3070171A1 (en) * | 2017-07-18 | 2019-01-24 | Merck Patent Gmbh | Tlr7/8 antagonists and uses thereof |
EP3728229A1 (en) * | 2017-12-19 | 2020-10-28 | Merck Patent GmbH | Tlr7/8 antagonists and uses thereof |
US10966999B2 (en) | 2017-12-20 | 2021-04-06 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
JP7098748B2 (ja) | 2017-12-20 | 2022-07-11 | インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール,ヴイ.ヴイ.アイ. | Stingアダプタータンパク質を活性化するホスホン酸結合を有する2’3’環状ジヌクレオチド |
WO2019123294A2 (en) * | 2017-12-22 | 2019-06-27 | Novartis Ag | Novel uses of pyrazolo piperidine derivatives |
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ES2962605T3 (es) | 2018-02-26 | 2024-03-20 | Gilead Sciences Inc | Compuestos de pirrolizina sustituidos como inhibidores de la replicación del VHB |
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MX2016004629A (es) | 2016-08-01 |
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IL267031A (en) | 2019-07-31 |
KR102365952B1 (ko) | 2022-02-22 |
RU2016118624A3 (sl) | 2018-04-25 |
IL267031B (en) | 2021-05-31 |
JP6483666B2 (ja) | 2019-03-13 |
KR20160068775A (ko) | 2016-06-15 |
EP3057948A1 (en) | 2016-08-24 |
CA2920791A1 (en) | 2015-04-23 |
JP2016539079A (ja) | 2016-12-15 |
AU2014334551B2 (en) | 2018-05-10 |
CN107935988A (zh) | 2018-04-20 |
IL243926B (en) | 2019-06-30 |
IL243926A0 (en) | 2016-04-21 |
US9663486B2 (en) | 2017-05-30 |
MX363708B (es) | 2019-03-29 |
ES2670550T3 (es) | 2018-05-30 |
BR112016008378A2 (sl) | 2017-10-03 |
CN105636945A (zh) | 2016-06-01 |
AU2014334551A1 (en) | 2016-02-25 |
EP3057948B1 (en) | 2018-03-14 |
CA2920791C (en) | 2021-11-16 |
RU2016118624A (ru) | 2017-11-17 |
CN105636945B (zh) | 2017-11-17 |
WO2015057655A1 (en) | 2015-04-23 |
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